title: TLR signaling is required for Salmonella typhimurium virulence.
abstract: Toll-like receptors (TLRs) contribute to host resistance to microbial pathogens and can drive the evolution of virulence mechanisms. We have examined the relationship between host resistance and pathogen virulence using mice with a functional allele of the nramp-1 gene and lacking combinations of TLRs. Mice deficient in both TLR2 and TLR4 were highly susceptible to the intracellular bacterial pathogen Salmonella typhimurium, consistent with reduced innate immune function. However, mice lacking additional TLRs involved in S. typhimurium recognition were less susceptible to infection. In these TLR-deficient cells, bacteria failed to upregulate Salmonella pathogenicity island 2 (SPI-2) genes and did not form a replicative compartment. We demonstrate that TLR signaling enhances the rate of acidification of the Salmonella-containing phagosome, and inhibition of this acidification prevents SPI-2 induction. Our results indicate that S. typhimurium requires cues from the innate immune system to regulate virulence genes necessary for intracellular survival, growth, and systemic infection.
authors.affiliation: Division of Immunology & Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720-3200, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Arpaia
authors.forename: Jernej
authors.initials: J
authors.lastname: Godec
authors.forename: Laura
authors.initials: L
authors.lastname: Lau
authors.forename: Kelsey E
authors.initials: KE
authors.lastname: Sivick
authors.forename: Laura M
authors.initials: LM
authors.lastname: McLaughlin
authors.forename: Marcus B
authors.initials: MB
authors.lastname: Jones
authors.forename: Tatiana
authors.initials: T
authors.lastname: Dracheva
authors.forename: Scott N
authors.initials: SN
authors.lastname: Peterson
authors.forename: Denise M
authors.initials: DM
authors.lastname: Monack
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Barton
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D012486:Salmonella typhimurium / Q000276:immunology* / Q000472:pathogenicity*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D008565:Membrane Proteins; C440638:SPI-2 protein, Salmonella; D051193:Toll-Like Receptors